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A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan
Seemin Seher Ahmed1, Huapeng Li, Chunyan Cao
11] Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA [2] Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Abstract:
Canavan's disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤ 1 month) AspA(-/-) mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno-associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. We demonstrate that systemically delivered and CNS-restricted rAAVs can serve as efficacious and sustained gene therapeutics in a model of a severe neurodegenerative disorder even when administered as late as P20.
Insights
Gene therapy using adeno-associated viruses (AAVs) offers hope for Canavan disease (CD). A single intravenous injection in mice models rescued lethality and improved symptoms, even when given late.
Area of Science:
- Neuroscience
- Genetics
- Biotechnology
Background:
- Canavan disease (CD) is a fatal pediatric leukodystrophy.
- Caused by mutations in the aspartoacylase (AspA) gene.
- No effective treatment currently exists for CD.
Purpose of the Study:
- Investigate gene therapy for Canavan disease using a mouse model.
- Evaluate the efficacy of recombinant adeno-associated viruses (rAAVs) for treating CD.
- Utilize miRNA-mediated detargeting to restrict gene expression to the central nervous system (CNS).
Main Methods:
- Studied progressive neuropathology in AspA(-/-) mice, a model for severe CD.
- Administered single intravenous injections of primate-derived rAAVs.
- Employed microRNA (miRNA)-mediated post-transcriptional detargeting.
Main Results:
- Single IV rAAV injections rescued early lethality and alleviated major CD symptoms in mice.
- Survival extended up to 2 years in treated groups.
- rAAV treatment improved CNS myelination, with restricted expression in the CNS.
Conclusions:
- Systemically delivered, CNS-restricted rAAVs are efficacious gene therapeutics for a severe neurodegenerative disorder model.
- Gene therapy can be effective even when administered late in the disease course.
- miRNA-mediated detargeting successfully minimized peripheral transgene expression.
